Ann Nucl Med (2009) 23:717–723
DOI 10.1007/s12149-009-0294-9

ORIGINAL ARTICLE

Vasodilatory effect of adenosine triphosphate does not change
cerebral blood flow: a PET study with 15O-water
Raihan Hussain Æ Tatsuro Tsuchida Æ Takashi Kudo Æ Masato Kobayashi Æ
Tetsuya Tsujikawa Æ Yasushi Kiyono Æ Yasuhisa Fujibayashi Æ Hidehiko Okazawa

Received: 30 June 2009 / Accepted: 28 July 2009 / Published online: 29 August 2009
Ó The Japanese Society of Nuclear Medicine 2009

Abstract
Objective Adenosine triphosphate (ATP) is the parent
compound of adenosine and well known as a powerfulvasodilator. To investigate the effect of ATP on cerebral
blood flow (CBF) and cerebral vessels, 15O-water positronemission tomography (PET) studies were performed toevaluate changes in CBF and blood volume before andafter ATP administration.
Methods Ten healthy young volunteers underwent
15
O-water PET scans under the conditions of baseline, 3
and 1 min after ATP continuous infusion. CBF values incortical regions of the bilateral middle cerebral arteries andbasal ganglia were obtained for each subject. Statisticalparametric mapping (SPM) was applied for analysis ofregional changes. Physiologic parameters, such as blood
gas and blood pressure were also measured.
Results Cortical CBF showed no significant change after
continuous infusion of ATP compared with the baseline.
Dilatation of major vessels induced by ATP was visualized
on SPM analysis. Heart rates increased and mean bloodpressure decreased during ATP administration while blood

R. Hussain  T. Kudo  M. Kobayashi  T. Tsujikawa 
Y. Kiyono  Y. Fujibayashi  H. Okazawa (&)
Biomedical Imaging Research Center (BIRC),
University of Fukui, 23-3 Shimoaizuki, Matsuoka,
Eiheiji-cho, Fukui 910-1193, Japane-mail: okazawa@u-fukui.ac.jp
T. Tsuchida
Department of Radiology, Faculty of Medical Sciences,
University of Fukui, Fukui, Japan
H. Okazawa
Research and Education Program for Life Science,
University of Fukui, Fukui, Japangas data showed no changes between the different
conditions.
Conclusions Intravenous ATP administration caused
dilatation of major cerebral vessels but no significant
change in CBF under normoventilation and decrease insystemic blood pressure, indicating that this no change in
CBF under vasodilatory effect of ATP may be caused by
cerebral microvascular autoregulation.
Keywords ATP  Cerebral blood flow  Vasodilation 
Cerebral autoregulation  Statistical parametric mapping

Introduction
Adenosine triphosphate (ATP) is a well-known vasodilator
for the skeletal and myocardial blood vessels [1, 2]. It is theparent compound of adenosine [3], and being widely used
for measurement of coronary flow reserve [4]. ATP has ashort plasma half-life (\20 s) and is rapidly metabolized toadenosine diphosphate (ADP), followed by adenosine
monophosphate (AMP), adenosine and finally allantoin [5].
Adenosine, the metabolic product of ATP, plays a role ofmaintaining vasodilation in the coronary and skeletalarteries [6], as well as an endogenous vasodilator for the
cerebral blood flow (CBF) regulation [7]. This effect may
be linked to the stimulation of adenylate cyclase and asubsequent increase in smooth muscle cyclic AMP, whichis mediated through an adenosine A2 receptor [8]. The
vasodilatory effect of ATP is mainly dependent on its
degradation to adenosine, yet the direct stimulation of
adenosine receptors by ATP itself was also reported [5].
Intravascular administration of adenosine induced
cerebral vasodilation in rabbits and baboons but did notwork in cats and dogs [9–13]. In human studies, adenosine

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administration increases CBF by cerebral vasodilation
under normoventilation [14, 15], which was assumed to be
counteracted by hyperventilation [14]. Dipyridamoleincreases effects of adenosine and causes a significant
decrease in CBF, although this effect is considered to becaused by hyperventilation [16]. Adenosine, dipyridamoleand ATP are all used as a pharmacologic stressor for
myocardial perfusion studies, and ATP is also used fortreatment of intracranial diseases, such as aftereffects ofhead injury and Meniere’s disease. To our knowledge,
however, it has not been investigated whether intravenous
ATP administration provides vasodilation of the humancerebral arteries and causing a change in CBF. The purposeof this study was to investigate effects of the intravenous
injection of ATP on CBF as well as the cerebral arteries inhuman. We studied changes in CBF after ATP administration using positron emission tomography (PET) and15
O-labeled water. The same procedure of ATP administration for examination of coronary flow reserve wasapplied in this study to evaluate cerebrovascular reaction
during myocardial SPECT studies.

Materials and methods
PET procedure
Ten healthy young male volunteers (age range: 20 to
31 years, mean: 24.0 ± 3.7 years) participated in thisstudy. The study received approval of our institutional
review board and written informed consent was obtained
from all subjects. All subjects were restricted caffeine andother methylxanthine containing foods or beverages for atleast 12 h before the study. They underwent 15O-water PET
scans with a whole body PET scanner (ADVANCE, GE
Medical Systems, Milwaukee, WI, USA), which permits
simultaneous acquisition of 35 image slices in a twodimensional acquisition mode with inter-slice spacing of
4.25 mm [17]. Performance tests showed the intrinsic
resolution of the scanner to be 4.6 to 5.7 mm in the trans-

H215O injection

Transmission

2 min

ES

10 min

ATP injectionES

5 m inH15
2 O

Fig. 1 Diagram of PET scans and timings ofand ATP
injections (vertical arrows). Transmission scan was performed for
10 min, followed by four emission scans (ES) with H15
2 O injection. At
the second scan, ATP injection was started 3 min before the start of123

axial direction and 4.0 to 5.3 mm in the axial direction. A
transmission scan was performed using 68Ge/68Ga forattenuation correction in each subject before tracer
administration. PET data were reconstructed using a Hanning filter with 6.0 mm full width at half maximum(FWHM) in the trans-axial direction.
The subjects were positioned properly on the PET tablewith an arterial line in the right arm and two venous lines in
the left arm. A bolus injection of 740 MBq H15
2 O was given
intravenously from one of the venous lines for each 2-min
PET scan. The arterial blood was drawn using a mini pump
(Perista mini-pump, Atto, Tokyo, Japan) with a rate of
7 mL/min for the first 90 s, followed by manual samplingof 0.5 mL blood at 90, 105 and 120 s. Radioactivity in thearterial blood drawn by the mini pump was counted continuously using an automatic radioactive counter (Apollo
Mec., Kobe, Japan). The arterial radioactivity concentration was calibrated by that of manually obtained arterial
blood. Decay of radioactivity from PET and blood data wascorrected to the starting point of each scan. Dispersion for
the external tube in the arterial radioactivity curve wascorrected with a double-exponential dispersion function.
CBF images were calculated from the PET data and arterial
blood curves by means of the autoradiographic method[18].
Four sequential H15
2 O-PET scans with 10-min intervals
were performed in each subject (Fig. 1). The first and thirdscans were baseline condition without ATP administration.
The second and fourth scans were performed during thecontinuous injection of ATP using the other venous linedifferent from that for 15O-water administration. The
injection rate of ATP was 0.16 mg/kg/min which is acommon dose used for myocardial perfusion studies. The
ATP injection continued during the 2-min PET scan. Since
ATP is administered continuously for 5 min and perfusion
tracer is injected at 3 min from the beginning to evaluate
flow reserve in myocardial perfusion studies, the second
scan was started at 3 min after the beginning of continuous
ATP infusion. To evaluate the earlier effect of ATP
administration, the fourth scan was started at 1 min after

10 minES

10 minES

3 m inemission scan and continued for 5 min (horizontal arrow). At the
fourth scan, ATP injection was started 1 min before the start ofemission scan

Ann Nucl Med (2009) 23:717–723

719

the beginning of ATP administration. Several physiologic
parameters, such as blood gas (PaCO2, PaO2), blood pressure and heart rate were also measured.
Data analysis and statistics
Subjects underwent a high-resolution MRI scan (192 slices,
1.6-mm thick, 0.8-mm pitch) using a Signa Excite scanner(3.0T, GE Medical System, Milwaukee, WI). Before drawing regions of interest (ROIs), CBF images were co-registered to the individual MRI image using an automatic
procedure [19]. Multiple circular ROIs of 10 mm in diameter
were placed in the cortical territories of bilateral middle
cerebral arteries using the co-registered individual MRI (12ROIs/slice 9 5 slices = 60 ROIs). Twelve ROIs in the same
size were also placed in the bilateral basal ganglia using twoor three corresponding slices. The regional CBF values wereaveraged for the cortex and the basal ganglia in each subject.
Cerebral vascular resistance (CVR) was also calculated by
dividing the mean blood pressure (MBP) with CBF(i.e. CVR = MBP/CBF). The MBP was calculated from theequation of MBP = (2DBP ? SBP)/2, where DBP and SBP
are diastolic and systolic blood pressure, respectively.
Changes in CBF were compared among the four conditions by the repeated measures analysis of variance(ANOVA). Physiologic values of blood pressure, heart rate
and CVR were also compared between baseline and postATP conditions by the repeated measures ANOVA with apost-hoc paired t test. Because blood gas data were measured only twice at the first baseline and at the end of thesecond scan with ATP administration, the difference
between the two conditions were analyzed by a paired t
test. A probability value of \0.05 was considered to indicate a statistically significant difference. Bonferroni correction for multiple comparison was applied to thethreshold probability value to keep an overall a = 0.05
when testing multiple null hypotheses. The CBF data werealso analyzed using statistical parametric mapping (SPM)[20, 21]. Two pairs of baseline and post-ATP conditions
were compared with SPM, i.e. the first versus the second
conditions and the third and the fourth conditions. In brief,
the t test was applied pixel-by-pixel to compare theregional differences in CBF among the different conditions. Comparison was performed between baseline andpost-ATP conditions. The t value for each pixel was thenconverted to a normal standard distribution (z-value),independent of the degree of freedom from error, constituting a statistical parametric map [21]. In the SPM analysis, each CBF image was smoothed using a Gaussian filter(12 mm FWHM) and the pixel values were normalized sothat the global mean of CBF should be 50 mL/min/100 g.
Analysis of covariance (ANCOVA) was used for evaluation of regional difference [20]. To identify the regions
showing significant differences, the height threshold (u)and the extent threshold (k) were set at p = 0.001 andk = 100, respectively [22].

Results
Table 1 shows the mean of CBF, blood pressure, heart rate
and CVR in different conditions in all subjects. Cortical CBF
values showed no significant difference even after intravenous ATP administration (54.0 ± 5.4 and 54.0 ± 6.1 mL/
100 g/min) compared to the baseline condition (56.0 ± 5.8
and 56.1 ± 5.4 mL/100 g/min) although the ATP injection
tended to induce a slight decrease (p = 0.743, repeatedmeasures ANOVA). CBF values in the bilateral basal ganglia regions were 59.0 ± 4.6 and 57.4 ± 5.9 at baseline,
58.1 ± 5.6 and 57.0 ± 6.2 (mL/100 g/min) at 3 and 1 min

Table 1 Changes in cerebral blood flow and physiological data
Parameters

3 min Post-ATP
Baselinea

1 min Post-ATP
Post-ATPp-value*

Baselinea

Post-ATPp-value*

CBF (mL/min/100 g)

56.0 ± 5.8

54.0 ± 5.4

ns56.0 ± 5.5

54.0 ± 6.1

ns

MBP (mmHg)

84.3 ± 5.7

78.8 ± 6.9\0.01

84.7 ± 6.1

79.3 ± 5.9\0.005

SBP (mmHg)

122 ± 11123 ± 14ns

123 ± 10123 ± 11ns

DBP (mmHg)

65.8 ± 5.1

56.6 ± 5.3\0.00165.8 ± 5.6

57.6 ± 5.2\0.001

HR (per min)62.3 ± 8.5

81.8 ± 9.1\0.00161.7 ± 7.5

82.3 ± 11.3

\0.001CVR

1.54 ± 0.22

1.48 ± 0.23

ns

1.52 ± 0.23

1.48 ± 0.18

ns

Repeated measures ANOVA applied for four conditions showed significant differences among four conditions in MBP (p \ 0.001), DBP and HR(p \ 0.0001)* p-values were calculated by the post-hoc paired t test
MBP mean blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure, HR heart rate, CVR cerebral vascular resistance, ns not
significantaBaselines are the first scan for 3 min post-ATP and the third scan for 1 min post-ATP

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after ATP administration, respectively, and there were no
significant difference between the conditions. Regarding
the physiologic data, heart rate showed significant
increases (p \ 0.0001), whereas MBP showed significant
decreases (p \ 0.001, repeated measures ANOVA) by 6.5%
at 3 min (p \ 0.01, paired t test) and 6.4% at 1 min

Table 2 Changes in blood gas data before and after ATP injection
Parameter

Baseline

Post-ATP (3 min)p-value*

PaCO2

41.4 ± 3.6

39.2 ± 2.1

0.13

PaO2

93.7 ± 9.4

96.1 ± 11.7

0.40

* p-values were calculated by paired t test

Fig. 2 SPM analysis forregional changes in CBF images
with transparent view (top left)
and overlying on six trans-axial
slices. a The regions ofsignificant differences between
3 min post-ATP administration
and baseline (post-ATP—baseline) correspond to thelocation of major vessels
including the circle of Willis.
b Similar but lesser differences
are demonstrated between
1 min post-ATP and baseline
conditions (post-ATP—baseline) representing major
vessels compared with the resultof 3 min post-ATP. No
significant difference wasobserved from the analysis ofbaseline—post-ATP. R
indicates right side of the brain123(p \ 0.005, paired t test) after the ATP injection compared tothe corresponding baseline. Systolic blood pressure did notchange, but diastolic blood pressure significantly decreased
after ATP administration (p \ 0.001, paired t test). Nochanges in CVR were observed in all conditions (Table 1).
PaCO2 and PaO2 did not show any significant changes
between pre- and post-ATP administration (Table 2).
The SPM analysis did not show any significant regionalchanges in CBF in the cortical regions, although significant
increases were revealed in the basal regions of the brain
after the ATP injection (Fig. 2). No regional decrease wasobserved by the analysis of baseline minus post-ATP
subtraction for both 3 and 1 min after injection. Superimposed slice sections showed that the regional differences

Ann Nucl Med (2009) 23:717–723

were corresponding to the major cerebral arteries. Areas ofdifference were larger at 3 min after continuous ATP
administration (Fig. 2a) compared with 1 min post-ATP(Fig. 2b).

Discussion
ATP, the parent compound of adenosine, has been introduced as a pharmacologic stressor for myocardial perfusion
studies [4]. In the present study, we tried to evaluate its
effects on the human major cerebral vessels and CBF. No
increase in cortical CBF, rather a slight non-significant
decrease, after the ATP injection was observed, althoughvasodilatory change at basal major vessels was indicatedaccording to SPM analysis. The relaxation of vascularsmooth muscles by the stimulation of the A2 receptors[7, 23] did not change CBF in the cerebral cortices, whichgoes in line with previous reports studied with adenosine[24, 25]. This no change in CBF despite vasodilation in the
major vessels is considered to be caused by systemic
hypotension due to vasodilation in peripheral arteries andthe cerebral microvascular autoregulation which preserves
intracranial perfusion pressure [22]. Vasodilatory changewith decrease in systemic blood pressure usually causes
reduction of blood flow; however, slight vasodilatorychange in major cerebral arteries may induce constrictionof arterioles and restore blood flow immediately by thewell-known function of microvascular autoregulation [22].
There was no change in CVR between different conditions
which supports this assumption.
The effect of ATP on CBF was different from that ofacetazolamide which causes an increase in CBF. Administration of acetazolamide is known to induce dilatation of
cerebral vessels, but it does not induce a decrease of systemic blood pressure, or rather induces a slight increase,which is considered to provide a CBF increase [26]. Several studies with human subjects or non-human primatesreported that the intracarotid injection of adenosine
increased CBF [13, 15, 27]. However, their injection
method may have caused dilatation of the cerebral vessels
only, which did not induce any significant effect on
peripheral arteries in the body. They observed no changes
in systemic blood pressure, which is different from ourresults showing decrease in systemic blood pressure
induced by intravenous ATP administration. Both MBP
and CBF tended to show decrease after ATP administration, although only MBP showed significant decrease.
CVR, a ratio of these two parameters, did not change
because the effect of the MBP decrease on CVR was
weakened by the small decrease in CBF. No change in
CVR was assumed to be caused by the physiologic function of autoregulation as mentioned above.

721

The SPM analysis showed significant difference in thebasal regions corresponding to the major cerebral arteries
including the circle of Willis, although ATP administration
did not induce regional CBF changes in the cerebral cortices. ATP causes generalized peripheral vasodilation
which includes the major arteries of the brain. The autoradiographic method for CBF calculation using H15
2 O
shows effects of vascular radioactivity on CBF images[28], and thus, SPM analysis shows regional changes not
only for CBF, but also for the vascular radioactivity due tochanges in regional blood volume. Elimination of earlyphase of PET data may have reduced this effect [28].
However, a single 2-min frame was employed for PET
acquisition in the present study because of the limitation of
ATP administration time (5 min or shorter), which prevented diminishing effects of vascular radioactivity. Direct
measurement of vascular volume would be ideal to evaluate vasodilatory change although we could not apply thetwo-compartment analysis in this study because the shortscan time of 2 min is not enough length for the analysis. In
the present study, however, SPM analysis for assessment ofchanges in intravascular radioactivity, which reflects
increase in blood volume, was able to visualize the ATP
effect on the cerebral vessels as the increase in radioactivity in the basal region. No significant change in cortical
CBF in quantitative values and the relative increase in
major vascular regions visualized by SPM indicated thevasodilatory effect of ATP without change in CBF. The
extent threshold of 100 cluster voxels was applied in thisstudy because effect of a drug on CBF and cerebral vessels
were evaluated, and thus, small change in extent should be
removed. A larger extent threshold could be applied, but
the regions of significant change was not significantly
different when k = 200 was applied.
Ito et al. [16] reported that dipyridamole, which increases
interstitial adenosine by inhibiting degradation of endogenous adenosine, caused significant decreases in CBF andPaCO2. They assumed that hyperventilation induced bydipyridamole caused CBF reduction, rather than a direct
effect of the drug on the cerebral arteries. Sollevi et al. [14]reported that intravenous administration of adenosine at adose of 0.2–0.5 mg/kg/min induced an increase in mean
CBF by 23–85% and decrease in mean CVR by 43–65% inpatients with normoventilation, and that this effect wascounteracted by hyperventilation observed in one patient. In
the present study, we administered ATP with a clinical dosefor coronary stress (0.16 mg/kg/min), which was lower thanthe previous studies used for adenosine. This lower dose of
ATP did not cause hyperventilation and all subjects in ourstudy showed no changes in PaCO2 during ATP administration. A longer ATP administration caused changes inbroader areas (Fig. 2), indicating that the longer stimulationof ATP induces the greater effect on large cerebral vessels.

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For measurement of coronary flow reserve with ATP, myocardial blood flow tracers are usually administered at 3 minafter the beginning of constant infusion of ATP as the protocol of the second condition in the present study. Thus, thetiming of the tracer injection is considered to be appropriate
to evaluate vasodilatory effect and flow reserve in myocardial SPECT studies.
There were reports of cerebrovascular accidents causedby an intracranial vascular steal phenomenon during
dipyridamole stress tests for the study of coronary flow
reserve [29, 30]. The vasodilatory effect of ATP also
induced systemic hypotension during continuous infusion,
however, the fact that the CBF was stable during ATP
administration indicates that ATP can be safely and adequately be used for coronary examinations with fewer side
effects, which is clinically important although all side
effects are well-tolerated and resolved spontaneously
within a few minutes after discontinuation [3]. The age
difference between younger healthy volunteers who participated in this study and the patients who have cardiovascular diseases and the need for further studies oncoronary flow reserve might be some of possible limitations. However, the result of this study showed that nochange in CBF presumably due to cerebral autoregulation
which is a basic physiologic function that should be preserved in older people as well.

Conclusion
Our results indicate that intravenous ATP administration
does not produce any significant change in cortical CBF
although the vasodilatory effect on the major cerebral
arteries was observed. This result was presumably caused
by decrease in systemic blood pressure and microvascular
autoregulation in the brain. The findings support safety andusefulness of ATP in clinical use for myocardial perfusion
studies or therapeutic managements.
Acknowledgments The authors thank staff of the Biological
Imaging Research Center, University of Fukui, for their technical andclinical support. This study was funded by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science(17209040, 18591334), and the 21st Century COE Program (Medical
Science).

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